Mature T-Cell and NK-Cell Neoplasm (BSH 2021, BSH 2011)

Intro

 

  • Mature or peripheral T-cell neoplasms are biologically and clinically varied

  • Result from clonal proliferation of post-thymic lymphocytes

  • Good prognosis = Anaplastic Lymphoma Kinase (ALK) positive anaplastic large cell (ALCL)

  • Most nodal and extra-nodal T-cell lymphomas however have 30% 5-year survival

  • Rare and lack phase 3 trial data due to low numbers.

 

WHO-HAEM5 CLASSIFICATION

Mature T-Cell and NK-Neoplasms

  • T-Prolymphocytic leukaemia

  • T-Large granular lymphocytic leukaemia

  • NK-Large granular lymphocytic leukaemia

  • Adult T-cell leukaemia/lymphoma (ATLL)

  • Sezary Syndrome

  • Aggressive NK-cell leukaemia

Anaplastic Large cell lymphoma

  • ALK+ anaplastic large cell lymphoma

  • ALK- anaplastic large cell lymhpoma

  • Breast implant-associated anaplastic large cell lymphoma

Nodal T-Follicular Helper (TFH) cell lymphoma

  • Nodal TFH cell lymphoma, angioimmunoblastic type

  • Nodal TFH cell lymphoma, follicular type

  • Nodal TFH cell lymphoma, NOS

Other peripheral T-cell lymphomas

  • Peripheral T-cell lymphoma, NOS

Several Other Categories (see link above)

  • Includes EBV associated, intestinal, hepatosplenic, primary cutaneous, precursor and tumour-like categories.

Epidemiology

 

10% of lymphoid malignancies

Incidence 1.7 / 100,000 / year

NK-Cell lymphomas more common in Asia and associated with EBV

Adult T-Cell leukaemia/lymphoma (ATL) associated with HTLV-1

 

Presentation & Diagnosis

 

Often present late with advanced stage, poor performance status and extra-nodal disease

Para-neoplastic features seen – eosinophilia, HLH, autoimmune processes

FBC, Biochem, LDH, B2M, CXR, CT, BM Biopsy

PET-CT staging (identifies additional sites of disease in 50% cases compared to CT)

 

Mature T-Cell Leukaemias

 

T-Prolymphocytic Leukaemia (T-PLL)

 

  • Post-Thymic T-cell malignancy

  • Rare. 2% of all small lymphocytic leukaemias

  • Median age at diagnosis: 61 years

  • Median OS: <2 years

  • Up to 30% pt have an indolent phase then clinically aggressive disease with WBC >100, serous effusions, skin infiltration, splenomegaly and lymphadenopathy

  • Immunophenotype

    • Mature T cell markers – CD2+, CD3 weak+, CD5+, CD7+ (Variable CD4 and CD8)

  • Cytogenetics & molecular

    • Complex kayotype & Chromosome 8 abnormalities common.

    • 90% show TCL1A/B and MTCP1 re-arrangements.

    • Association with ataxia telangiectasia (ATM gene disruption (11q22.3))

  • Treatment

    • Watchful waiting of asymptomatic cases

    • 1st line therapy: IV Alemtuzumab. Transplant in first remission.

    • PCP and shingles prophylaxis. CMV PCR monitoring

    • (Marsden Hospital Cohort – 125 pt. Rx’d with IV Campath. CR 50%, PR21%. Median OS 16 months. 5-yr OS 32% for transplanted patients (mix of allo and auto))

 

T/NK-Large Granular Lymphocytic Leukaemia (LGLL)

 

  • Persistent clonal expansion of large, granular T (80%) or NK cells

  • Median age of diagnosis: 66 years

  • Associated with AI disorders, e.g. rheumatoid arthritis

  • Indolent, median survival >10 years

  • Most patients develop severe neutropenia (soluble Fas ligand released from LGL’s induces neutrophil apoptosis). Also other cytopenias, hepatosplenomegaly.

  • Immunophenotype

    • CD3+, TCRαβ+, CD8+, CD16+, CD57+, CD94+, KIR+, CD56-

  • Molecular

    • STAT3 mutation in 30-40% (occurs as a 2o event in an already expanding clone)

  • Treatment

    • Treat if complications from cytopenias

    • 1st line: Ciclosporin or low dose methotrexate + GCSF/Epo

    • Goal of Rx: Reducing or silencing clone will restore counts. Not necessary to eliminate it.

  

Adult T-Cell Leukaemia/Lymphoma (ATLL)

 

  • Caused by HTLV-1, which is epidemic in Japan, Africa, South America

  • Median age of diagnosis: 53 years

  • Subtypes – leukaemic, lymphoma, skin, chronic & smouldering

  • Median OS: 8-10 months for acute vs 2-4 years for indolent subtypes

  • Immunophenotype

    • CD3+, CD4+, CCR4+, CD25+, CD26- CD7-

  • Molecular

    • Mutations in genes relating to immune evasion - CTLA4::CD28, ICOS::CD28, REL, HLA-A/B, PD-L1

    • STAT3 mutations more common in indolent presentations

  • Treatment - General

    • Screen 1st degree relatives & partners for HTLV-1 due to their increased risk

    • Check for strongyloides at diagnosis

    • Prophylaxis against opportunistic infection

    • Consider all patients for early allograft in first CR

  • 1st line therapy - General

    • Nodal & acute disease - CHOP-based chemotherapy

    • Sking, smouldering & chronic - Zidovudine + Interferon-alfa

    • Mogamulizumab - Anti-CCR4 monoclonal Ab - most active in leukaemic disease

Aggressive NK-cell leukaemia

 

  • More common in Asia and almost always associated with EBV

  • Acute presentation with fever, jaundice, LNadenopathy, organomegaly

  • Patients are sick, may have DIC / HLH / MOF

  • Immunophenotype

    • CD3episilon+, CD56+, CD16+, CD2-, sCD3-, CD57-

  • Molecular

    • JAK/STAT and RAS/MAPK pathway mutations, TET2, KMT2D, CREBBP, PD-L1, PD-L2

  • OS 2 months

  • 1st line: Clinical trial, ALL-type therapy

 

Nodal PTCL

Notes

  • BM involvement present in 35% of cases (PET-CT not very good at identifying this)

  • Outside BM, the nodal disease is almost always FDG-avid on PET-CT 

Peripheral T-Cell Lymphoma, NOS (PTCL-NOS)

 

  • Largest group, 50% of T-cell cases

  • Includes ‘Follicular T-cell lymphoma’ and ‘Nodal peripheral T-cell lymphoma with a T-follicular helper (Tfh) phenotype’ which are new in the WHO 2016. Pathophysiology overlaps with AITL.

  • Aggressive, usually nodal

  • 5-yr OS: 30%

  • 1st line therapy:

    • Clinical trial, otherwise CHOP but disappointing results. ?Autograft in 1st CR.

    • Allograft data discussed in the guideline

 

Angio-Immunoblastic T Cell Lymphoma (AITL)

 

  • A disease of the elderly

  • Presentation often mimics an infectious process

  • Sometimes spontaneously regresses

  • Pathophysiology overlaps with PTCL-NOS

  • Molecular

    • TET2, DMNT3A, RHOA and IDH2 mutations

  • 5-yr OS: 30%

  • 1st line therapy: Trial, otherwise CHOP. ?Autograft in 1st CR.

 

Anaplastic Large Cell Lymphoma (ALCL)

 

  • Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase, usually only found in CNS.

  • NPM1-ALK fusion gene defines ALK+ ALCL

  • ALK+ significantly better prognosis than ALK-. Though ALK- still better than PTCL-NOS

  • Four subtypes

    • 1o systemic ALK+, 1o systemic ALK-, 1o cutaneous and breast-implant associated

    • Different pathophys and different clinical responses

  • Median age of diagnosis: ALK+ 30 years, ALK- 55 years

  • Typically present at advanced stage with B symptoms

  • Treatment: advanced stage ALCL:

  • Treatment: Breast implant-associated ALCL

    • Surgical resection may be curative

  • Treatment: Cutaneous ALCL

    • Local excision +/- radiotherapy

 

Extra-Nodal PTCL

 

Extranodal NK/T-Cell Lymphoma (ENKTL)

 

  • Aggressive, EBV+

  • More common in East Asia and S. America

  • Median age at diagnosis: 50-60 years

  • Classically presents in nasal structure but nodal or BM involvement can be present

    • E.g.Presents as adult male with facial oedema, nasal obstruction and epistaxis

  • 5-yr OS: 56% nasal, 34% extra-nasal

  • Prognostic score: PINK

  • Immunophenotype

    • NK phenotype: CD2+, CD56+, CD3epislon+ (and CD8+ variants)

  • Treatment:

    • Clinical Trial

    • Localised: Radiotherapy + Chemotherapy (e.g. GELOX, LVDP, DeVIC)

    • Advanced Stage: DDGP, SMILE (high toxicity). HSCT in 1st CR

Aggresive NK-Cell Leukaemia (ANKL)

  • Very rare. More prevalent in Asian countries

  • Median age of diagnosis: 40 years

  • DIC, HLH, Mulit-organ failure present at diagnosis

  • Median OS: 36 days without allograft, 266 days with allograft

 

Aggressive Intestinal T-Cell Lymphoma

 

  • Aggressive, ulcerating large cell tumours of the small bowel

  • Diarrhoea, Abdo pain, Weight loss

  • Median age at diagnosis: 62 years

  • Enteropathy associated T-cell lymphoma (EATL)

    • Almost always associated with (HLA)-DQ2 or (HLA)-DQ8, and coeliac disease

    • alpha-betaTCR+, CD30+, CD4-, CD8-, CD56-

  • Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)

    • Formerly known as EATL type II

    • Not associated with coeliac. More common in Asian and Hispanic countries

    • gamma-deltaTCR+, CD8+, CD56+

  • Median OS: 7 months

  • Treatment

    • MDT with gastro and nutrition teams

    • Clinical trial

    • 1st line therapy: No satisfactory treatment. CHOP + Autograft

    • Treatment can be intensified with NCRI/SNLG protocol

 

Hepatosplenic T-Cell Lymphoma (HSTL)

 

  • Aggressive disease. Used to be considered disease of young age but wider spread now reported

  • Associated with post solid organ transplant or immunosuppression

  • BM biopsy morphology often mimics myelodysplasia

  • Often 7q abnormality

  • Historical median OS: 16 months

  • Treatment

    • Intensive chemo (IVE/ICE) followed by allograft in 1st CR

 

Subcutaneous pannciulitis-like T-Cell Lymphoma (SPTCL)

 

  • Presents as subcutaneous tumour nodules at any age.

  • Not universally aggressive. Consider CHOP / radiotherapy

a few trial notes

ECHELON-2 2018

  • 600 patients, Phase 3, placebo-controlled

  • Brentuximab + CHP (A-CHP) vs CHOP

  • Most patients had anaplastic large cell lymphoma (but any CD30+ peripheral T-cell eligible)

  • Median PFS 48 months for A-CHP vs 20 months for CHOP

  • OS advantage